The aging of the brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's[unreadable] and Parkinson's disease. An exciting recent development is the elucidation of a pattern of DNA damage in[unreadable] the aging human brain that is associated with reduced expression of genes that mediate synaptic plasticity,[unreadable] vesicular transport and mitochondrial function. Our finding of a "genetic signature" of brain aging that can be[unreadable] explained, at least in part, by oxidative DMA damage to vulnerable gene promoters provides a novel[unreadable] conceptual framework for understanding how the brain ages. Furthermore, we have begun to define the[unreadable] mechanism by which damaged genes are silenced by obtaining evidence for the involvement of a nuclear[unreadable] protein complex that contains the transcriptional co-repressor NCOR1, the human ortholog of the yeast[unreadable] ongevity gene SIR2 (Sirt1), and the DNA repair enzyme hOGG1. Our preliminary studies also suggest that[unreadable] this age-related process may be accelerated in Alzheimer's disease, and may predispose to aggregation of[unreadable] amyloid beta-protein (Abeta). These findings provide the basis for our hypothesis that DNA damage contributes to[unreadable] reduced expression of important neuronal genes in the aging brain, and that this process may underlie[unreadable] cognitive decline and vulnerability to neurodegeneration. The studies in this proposal will establish a[unreadable] genome-wide database of gene expression and DNA damage in the normal aging human brain. The[unreadable] mechanisms of selective DNA damage and gene silencing in the aging brain will be investigated, and the[unreadable] role of the newly defined DNA damage silencing complex involving Sirt1 (Project 3) will be defined.[unreadable] Transgenic mice that oyerexpress DNA repair enzymes will be generated to determine whether DNA[unreadable] damage contributes to age-related cognitive decline. These mice will also be mated with APPsw and Ck-p25[unreadable] transgenic mice generated in Project 2 to determine the role of age-related DNA damage in the pathology of[unreadable] Alzheimer's disease. These studies may provide new insights into brain aging, with potentially significant[unreadable] therapeutic implications.